PDF is a metallopeptidase found in prokaryotic organisms, such as bacteria. Protein synthesis in prokaryotic organisms begins with N-formyl methionine (fMet). After initiation of protein synthesis, the formyl group is removed by the enzyme PDF; this activity is essential for maturation of proteins. It has been shown that PDF is required for bacterial growth. See Chang et al., J. Bacteriol., Vol. 171, pp. 4071-4072 (1989); Meinnel et al., J. Bacteriol., Vol. 176, No. 23, pp. 7387-7390 (1994); and Mazel et al., EMBO J., Vol. 13, No. 4, pp. 914-923 (1994). Since protein synthesis in eukaryotic organisms does not depend on fMet for initiation, agents that will inhibit PDF are attractive candidates for development of new anti-microbial and anti-bacterial drugs.
Co-pending application Ser. No. 10/171,706, filed Jun. 14, 2002 (incorporated herein by reference in its entirety), PCT equivalent published as WO 02/102790 A1, discloses novel N-formyl hydroxylamine compounds that inhibit PDF and are therefore useful as antibacterial agents. The compounds disclosed therein are certain N-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl}(carbonylamino-aryl or -heteroaryl)-azacyclo4-7alkanes or thiazacyclo4-7alkanes, which are described in more detail hereinafter. Additionally, PCT application WO 99/39704 discloses other N-formyl hydroxylamine derivatives that are antibacterial agents by virtue of their PDF inhibiting capabilities. Improved processes have been discovered for preparing intermediates useful for preparing these N-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl}(carbonylamino-aryl or -heteroaryl)-azacyclo4-7alkanes or thiazacyclo4-7alkanes, which have one or more of the following features: (1) make use of a particular β-lactam intermediate; (2) which make use of particular resolving agents, e.g., enantiomerically pure substituted propionic acids, especially (R)-2-butyl-3-hydroxy-propionic acid; (3) which avoid the use of hydrogen peroxide (the use of hydrogen peroxide can be a safety concern because of its instability, therefore, this aspect of the invention is safer than the prior art process); and (4) which facilitate selective debenzylation, reducing production of waste by-products.